PepGen Reports Positive Topline Results from Lowest-Dose (5 mg/kg) MAD Cohort in Phase 2 FREEDOM2 Study, Highlighting Safety, Splicing, and vHOT Outcomes
PepGen has reported encouraging topline results from the lowest-dose cohort (5 mg/kg) in its ongoing Phase 2 FREEDOM2 study, evaluating PGN-EDODM1 in patients with myotonic dystrophy type 1 (DM1). The data highlight a favorable safety and tolerability profile, along with early signals of biological and functional activity, supporting continued development of the therapy at higher dose levels.
The FREEDOM2 study is a randomized, placebo-controlled, multiple ascending dose (MAD) Phase 2 clinical trial designed to assess the safety, pharmacodynamics, and potential efficacy of PGN-EDODM1. The therapy is an investigational oligonucleotide-based treatment aimed at addressing the underlying genetic cause of DM1, a debilitating neuromuscular disorder characterized by progressive muscle weakness and multisystem complications. PepGen’s broader goal is to advance next-generation oligonucleotide therapeutics capable of transforming treatment paradigms for severe neuromuscular and neurological diseases.
In this cohort, eight patients were enrolled and randomized in a 6:2 ratio to receive either PGN-EDODM1 at a dose of 5 mg/kg or placebo. Dosing occurred every four weeks over a 12-week period. The data cutoff for this analysis was March 4, 2026. Key endpoints included safety, splicing correction—a molecular measure of disease modification—and functional outcomes such as vHOT (video hand opening time), 10-meter walk/run test (10MWRT), and handgrip strength.
From a safety standpoint, PGN-EDODM1 demonstrated a strong profile. The treatment was generally well tolerated, with no serious adverse events reported. All treatment-emergent adverse events (TEAEs) considered related to the drug were mild in severity, while unrelated TEAEs were either mild or moderate. Importantly, there were no discontinuations due to adverse events, no evidence of renal toxicity, and no signs of cumulative toxicity over the dosing period. Nausea was the most commonly reported adverse event, but it remained manageable and did not raise significant concerns.
These findings are particularly notable given the challenges often associated with oligonucleotide therapies, including potential safety liabilities related to repeated dosing. The absence of serious or dose-limiting toxicities at this early stage provides a solid foundation for continued dose escalation and longer-term evaluation.
On the efficacy side, the results showed promising, albeit preliminary, biological activity. Among the six patients treated with PGN-EDODM1, the mean splicing correction was 7.3%, compared to 6.8% observed in the placebo group. While this difference appears modest at first glance, a deeper analysis revealed the impact of a single outlier patient. This individual experienced a worsening in splicing correction of 70.8%, which significantly skewed the overall average. When this outlier was excluded, the mean splicing correction among treated patients increased substantially to 22.9%, suggesting a more meaningful treatment effect in the majority of participants.
Splicing correction is a critical biomarker in DM1, as the disease is driven by toxic RNA transcripts that disrupt normal RNA processing. Improvements in splicing are therefore considered indicative of a therapy’s ability to address the root cause of the condition. The observed levels of correction, particularly after adjusting for the outlier, are encouraging and support further investigation at higher doses.
Additional pharmacokinetic data also supported the biological activity of PGN-EDODM1. Muscle tissue concentrations of the drug were measured in five of the six treated patients approximately one week after the fourth dose. The mean concentration was 158 ng/g, indicating effective delivery of the therapy to target tissues. One measurement remains pending, but the available data suggest consistent tissue exposure across patients.
Functional outcomes provided further insight into the potential clinical impact of the therapy. In the vHOT assessment, which measures hand opening speed and is considered a relevant functional endpoint in DM1, patients in the treatment group showed a positive trend toward improvement. In contrast, patients receiving placebo exhibited a worsening trend. However, both groups returned to baseline levels by Week 16, indicating that the observed changes may be transient or require higher doses or longer treatment duration to sustain.
No meaningful improvements were observed in other functional measures, including the 10MWRT and handgrip strength. This is not unexpected given the relatively low dose and short duration of treatment in this cohort. Functional improvements in neuromuscular diseases often lag behind molecular changes and may require prolonged exposure or higher dosing to become apparent.
Overall, the totality of data from the 5 mg/kg cohort suggests that PGN-EDODM1 is biologically active and well tolerated, with early signs of efficacy that warrant further exploration. The company believes these findings support the continued evaluation of higher dose levels, particularly the ongoing 10 mg/kg cohort.
PepGen has reported that the 10 mg/kg MAD cohort is actively enrolling and progressing as planned. To date, five of the eight patients in this cohort have received up to three doses of PGN-EDODM1. The company expects to report clinical data from this group in the second half of 2026. This next readout will be critical in determining whether increased dosing can enhance splicing correction and translate into more robust and sustained functional improvements.
In addition to the core study, PepGen is also advancing an open-label extension (OLE) phase, which allows participants to continue receiving the therapy beyond the initial study period. Currently, 12 patients have enrolled in the OLE at the 5 mg/kg dose, including five individuals who previously participated in FREEDOM2. This extension will provide valuable long-term safety and efficacy data, helping to inform future development and potential regulatory pathways.
Financially, the company remains in a strong position to support its clinical programs. PepGen has indicated that its current cash reserves are sufficient to fund operations into the second half of 2027. This runway provides the company with the flexibility to complete ongoing trials, analyze upcoming data, and potentially initiate additional studies as needed.
The company also announced that it will host a conference call to discuss the results and provide further updates on its development pipeline. The webcast will be available through PepGen’s investor relations website, with a replay accessible after the event.
In summary, the topline results from the 5 mg/kg cohort of the FREEDOM2 study represent an important milestone for PepGen and its PGN-EDODM1 program. The therapy demonstrated a favorable safety profile, encouraging levels of splicing correction when accounting for variability, and early signs of functional benefit. While additional data from higher doses and longer follow-up are needed to fully assess its clinical potential, the current findings provide a strong rationale for continued development. As the study progresses, the upcoming results from the 10 mg/kg cohort will be closely watched as a key indicator of the therapy’s potential to deliver meaningful benefits to patients with DM1.
About PGN-EDODM1
PGN-EDODM1, PepGen’s investigational candidate in development for the treatment of DM1, utilizes the Company’s proprietary EDO technology to deliver a therapeutic oligonucleotide that is designed to restore the normal splicing function of MBNL1, a key RNA splicing protein. PGN-EDODM1 addresses the deleterious effects of cytosine-uracil-guanine (CUG) repeat expansion in the dystrophia myotonica protein kinase (DMPK) transcripts which sequester MBNL1, by binding to the pathogenic CUG trinucleotide repeat expansion present in the DMPK transcripts, and disrupting the binding between the CUG repeat expansion and MBNL1. PepGen believes this innovative therapeutic approach may have considerable advantages over oligonucleotide modalities that rely on knockdown or degradation of the DMPK transcripts as it will allow the DMPK transcripts to continue to perform their normal function within the cell, while also liberating MBNL1 to correct downstream mis-splicing events. The U.S. Food and Drug Administration has granted PGN-EDODM1 both Orphan Drug and Fast Track Designations for the treatment of patients with DM1. The European Medicines Agency (EMA) has recently granted Orphan Designation for PGN-EDODM1.
About PepGen
PepGen Inc. is a clinical-stage biotechnology company developing the next generation of oligonucleotide therapies with the goal of transforming the treatment of severe neuromuscular and neurological diseases. PepGen’s Enhanced Delivery Oligonucleotide (EDO) platform is founded on over a decade of research and development and leverages cell-penetrating peptides to improve the uptake and activity of conjugated oligonucleotide therapeutics. Using these EDO peptides, the Company is generating a pipeline of oligonucleotide therapeutic candidates designed to target the root cause of serious diseases.
